l features related to fetal alcohol syndrome in 5-year-old

Are Low-to-Moderate Average Alcohol Consumption and Isolated Episodes of Binge Drinking in Early Pregnancy Associated with Facial Features Related to Fetal Alcohol Syndrome in 5-Year-Old Children?

Ulrik Schiøler Kesmodel, Siv Steffen Nygaard, Erik Lykke Mortensen, Jacquelyn Bertrand, Clark H. Denny, Alex Glidewell, Susan Astley HemingwayDepartment of Obstetrics and Gynecology, (USK, SSN), Herlev University Hospital, Herlev, Denmark; Department of Clinical Medicine, (USK), University of Copenhagen, Copenhagen, Denmark; Center for Healthy Aging, (ELM), Institute of Public Health, University of Copenhagen, Copenhagen, Denmark; Centers for Disease Control and Prevention (CDC), (JB, CHD), Atlanta, Georgia; University of Washington, (AG), Seattle, Washington; and Departments of Epidemiology and Pediatrics, (SAH), University of Washington, Seattle, Washington.

Abstract

Background: Fetal alcohol syndrome (FAS) typically is observed among individuals with high

prenatal alcohol exposures (PAE), but exposure histories obtained in clinical diagnostic settings

are often inaccurate. The present analysis used the Lifestyle During Pregnancy Study (LDPS) to

assess the potential effects of low-to-moderate average weekly alcohol consumption and binge

drinking in early pregnancy on facial features associated with FAS among children 5 years of age.

Methods: The analysis is a prospective follow-up study of 670 women and their children

sampled from the LDPS cohort based on maternal alcohol consumption during pregnancy. The 4-

Digit Code FAS Facial Photographic Analysis Software was used to measure the magnitude of

expression of the 3 diagnostic facial features of FAS from standardized digital photographs.

Logistic regression was used to estimate the odds of presenting with the FAS/partial fetal alcohol

syndrome (PFAS) facial phenotypes relative to different patterns of prenatal alcohol exposure.

Results: Ten children presented with the FAS/PFAS facial phenotypes. None of the children

sampled met the central nervous system (CNS) criteria for FAS or PFAS at age 5 years. All

remained at risk for PFAS since some types of CNS dysfunction associated with this diagnosis

Reprint requests: Ulrik Schiøler Kesmodel, Department of Obstetrics and Gynecology, Herlev University Hospital, PhD, University of Copenhagen, Herlev Ringvej 75, Herlev, Denmark; Tel.: +45 3020 6850; [email protected].

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

CONFLICT OF INTERESTNone.

ETHICSThe LDPS was approved by the DNBC Board of Directors, the DNBC Steering Committee, the Regional Ethics Committee, the Danish Data Protection Agency, and the Institutional Review Board at the Centers for Disease Control and Prevention. Signed informed consent was obtained for the LDPS. The current analyses were approved by the DNBC Steering Committee and the Danish Data Protection Agency.

HHS Public AccessAuthor manuscriptAlcohol Clin Exp Res. Author manuscript; available in PMC 2019 August 13.

Published in final edited form as:Alcohol Clin Exp Res. 2019 June ; 43(6): 1199–1212. doi:10.1111/acer.14047.

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may only be assessed at older ages. The FAS/PFAS facial phenotypes were 8.5-fold more likely

among children exposed to an average of 1 to 4 drinks/wk and 2.5-fold more likely among

children with a single binge exposure in gestational weeks 3 to 4 compared to children with no

such exposures. The magnitude of expression of the FAS facial phenotype was significantly

correlated with all other diagnostic features of FAS: growth deficiency, microcephaly, and

measures of CNS dysfunction.

Conclusions: These findings suggest that low-to-moderate levels of PAE or isolated binge

exposures may place some fetuses at risk for FAS/PFAS. Thus, conservative advice is still for

women to abstain from alcohol consumption during pregnancy.

Keywords

Alcohol; Alcohol Binge Drinking; Pregnancy; Fetal Alcohol Syndrome; Fetal Alcohol Spectrum Disorders

Fetal alcohol syndrome (fas) is a permanent birth defect and developmental disability caused

by in utero exposure to alcohol. FAS is characterized by growth deficiency, a unique

constellation of minor facial anomalies, and structural, neurological, or functional central

nervous system (CNS) abnormalities (Astley and Clarren, 2000; Bertrand et al., 2004;

Stratton et al., 1996). Not all individuals exposed to and damaged by prenatal alcohol

exposure have FAS, the most involved diagnosis under the umbrella of fetal alcohol

spectrum disorders (FASDs). Prenatal exposure to alcohol can also result in more subtle

adverse effects and diagnoses. The growth, facial, and CNS abnormalities can all present

along separate continua from mild to severe (Stratton et al., 1996).

A number of FASD diagnostic schemes have been posed and applied worldwide (Astley,

2004; Bertrand et al., 2004; Bower and Elliott, 2016; Cook et al., 2016; American

Psychiatric Association, 2013; Hoyme et al., 2016). All promote an interdisciplinary

approach to diagnosis and broadly agree that FASDs are characterized by growth, facial, and

CNS abnormalities. But, the specific criteria used to define each diagnosis under the

umbrella of FASDs do differ across the diagnostic systems (Astley, 2011; Astley et al., 2017;

Coles et al., 2016). It should be noted that all schemes assess facial features for an FAS

diagnosis since these features reflect anomalies in prenatal brain development. The current

analysis used criteria as outlined in Astley (2004), also known as the 4-Digit Code. Briefly,

these criteria require all of the following:

1. Growth deficiency: prenatal and/or postnatal height and/or weight at or below the

10th percentile;

2. Facial dysmorphia: all 3 of the following: (i) short palpebral fissure lengths

(PFLs; less than or equal to third percentile); (ii) smooth philtrum (Rank 4 or 5

on the University of Washington Lip-Philtrum Guide); and (iii) thin upper lip

(Rank 4 or 5 on the University of Washington Lip-Philtrum Guide);

3. Evidence of severe CNS structural, neurological, and/or functional

abnormalities;

Schiøler Kesmodel et al.

Alcohol Clin Exp Res. Author manuscript; available in PMC 2019 August 13.

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4. Prenatal alcohol exposure: a confirmed or unknown history of exposure. FAS can

be diagnosed in the absence of a confirmed prenatal alcohol exposure history if

the 3 facial features (as defined by the Rank 4 facial phenotypes in the 4-Digit

Code) are present. Empirical evidence confirms the Rank 4 facial phenotypes are

so highly specific to (caused only by) prenatal alcohol exposure. Its presence can

be used to confirm exposure when an exposure history is unavailable (Astley,

2013).

The FAS facial phenotype is not simply present or absent. It presents along a clinically

meaningful continuum from mild to moderate to severe (Astley and Clarren, 2000). The

magnitude of expression of the FAS facial phenotype not only increases with increasing

prenatal alcohol exposure, but also correlates significantly with increasing severity of growth

deficiency, microcephaly, and CNS dysfunction (Astley, 2013). These significant

correlations serve to validate a causal association between prenatal alcohol exposure and the

growth, facial, and CNS abnormalities currently used to define FAS (Astley, 2013; Astley

and Clarren, 2001).

FAS is typically observed among individuals with reportedly high prenatal alcohol

exposures (PAE; ≥6 drinks/d or 5 to 6 drinks within a short period of time) (O’Leary and

Bower, 2012), but exposure histories obtained in clinical diagnostic settings often are

inaccurate. For example, the average reported exposure among 154 individuals diagnosed

with FAS or partial fetal alcohol syndrome (PFAS) at the University of Washington FAS

Diagnostic & Prevention Network (FASDPN) using the 4-Digit Code was 8 to 12 drinks per

drinking occasion, 5 to 6 days per week (Astley, 2010). This average exposure pattern,

however, spanned a wide range. At the low end of the range, 1 of every 14 children with

FAS or PFAS had a reported exposure of no more than 1 drink/d. Are these 1 in 14 cases

especially vulnerable to the adverse effects of prenatal alcohol exposure, or were their lower

exposures inaccurately reported? The Lifestyle During Pregnancy Study (LDPS) (Kesmodel

et al., 2010, 2012) provided just such a dataset that addressed this issue by collecting

prenatal alcohol exposure history during early pregnancy and using standardized measures

of growth, face, and CNS.

The LDPS has previously provided data on the association between low-to-moderate alcohol

intake and alcohol binge drinking and neuropsychological development, including

intelligence, attention, psychomotor function, executive function, and behavior (Bay et al.,

2012; Kesmodel et al., 2010, 2012, 2013). The objective of the present analysis was to use

the LDPS to assess the potential effects of low-to-moderate average weekly alcohol

consumption and binge drinking in early pregnancy on facial features associated with FAS

among children 5 years of age. Specifically, we (i) document the occurrence of the

individual FAS facial features and overall FAS facial phenotype in the study sample; (ii)

assess the association between prenatal alcohol exposure and the magnitude of expression of

the FAS facial features and phenotype; and (iii) assess the association between the

magnitude of expression of the FAS facial phenotype and other diagnostic features of FAS,

including cognitive impact, reduced head circumference, and growth deficiency.



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MATERIALS AND METHODS

Study Sample

This study was part of the LDPS, which has been described in detail elsewhere (Kesmodel et

al., 2010, 2012). Briefly, the study is a prospective follow-up study based on a subsample

from the Danish National Birth Cohort (DNBC; Olsen et al., 2001).

A total of 1,628 mother–child pairs participated in the follow-up. Inclusion was based on a

stratified sample with oversampling of women with low-to-moderate alcohol intake and

binge drinking (Kesmodel et al., 2010, 2012). Exclusion criteria were inability to speak

Danish, impaired hearing or vision causing inability to complete the cognitive tests, multiple

pregnancies, and congenital diseases likely to cause mental retardation (Kesmodel et al.,

2010). Data collection for the follow-up study took place from September 2003 to June 2008

(Kesmodel et al., 2010).

Of the 1,628 participants’ images available for measurement, 670 met the inclusion criteria

for this study and had at least 1 of the 3 facial features measured (see details in Appendix).

Exposure Assessment

Information on alcohol intake during pregnancy was derived from the first prenatal DNBC

interview. Among the subsample of women participating in the follow-up, the median week

of gestation for completing the prenatal interview was 17 weeks (range: 7 to 39 weeks).

During the interview, the women were asked about their average number of beers, glasses of

wine, and glasses of spirits they currently consumed at the time of the interview over the

course of a week, and based on this information, the total number of weekly drinks was

calculated. These alcohol exposure questions have been shown to yield valid estimates of

alcohol consumption throughout pregnancy (relative to other methods) and reliable

information among pregnant Danish women (Kesmodel and Olsen, 2001). Information on

binge drinking during pregnancy included data on the number of binge episodes (defined as

intake of ≥5 drinks on a single occasion) and the timing (gestational week) of these episodes

(Kes-model, 2001) up until the time of the interview. A number of women in the current

sample reported 1 or more binge episodes during early weeks of pregnancy, although their

average number of drinks per week at the time of interview was zero (Kesmodel et al.,

2012). These women were classified accordingly as consuming zero average drinks per

week during pregnancy, but with 1 or more previous binge episodes. The definition of a

drink followed the definition from the Danish National Board of Health, with 1 standard

drink being equal to 12 g of pure alcohol. The sampling stratification for average weekly

consumption and binge consumption in the first trimester has been described previously

(Kesmodel et al., 2010, 2012). This stratification resulted in 5 sampling categories used in

this analysis.

Outcome Measures

Facial Features.—The follow-up assessments were conducted at 4 sites located in

Copenhagen, Aarhus, Odense, and Aalborg. The assessment comprised a comprehensive



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neuropsychological test battery which is described in detail elsewhere (Kesmodel et al.,

2010, 2012).

Following the test session, standardized digital facial photographs were taken of each mother

and child to allow subsequent measurement of (dysmorphic) facial features, including the

philtrum, the upper lip, and PFL. Specific procedures for taking and coding photographs are

described in Appendix. All testers were blind to the exposure status of the participants, and

all tests were administered in Danish.

Briefly, the University of Washington FAS Facial Photographic Analysis Software (Astley,

2016) was used to measure the magnitude of expression of each of the 3 diagnostic facial

features of FAS (short PFLs: 2 or more standard deviations (SD) below the mean; smooth

philtrum (Rank 4 or 5 on the University of Washington Lip-Philtrum Guide) and thin upper

lip (Rank 4 or 5 on the Lip-Philtrum Guide (Fig. 1), lip circularity ≥75.5) as defined by the

University of Washington FASD 4-Digit Code (Astley, 2016). For the 366 children with

photographs of sufficient quality to allow accurate measurement of all 3 facial features, the

magnitude of expression of the overall FAS facial phenotype (Face Rank) was ranked on a 4-

point Likert scale (Rank 1: normal phenotype; Rank 2: mild FAS phenotype; Rank 3:

moderate FAS phenotype; and Rank 4: severe FAS phenotype) in accordance with the FASD

4-Digit Code (Astley, 2004). The Scandinavian PFL growth charts (Stromland et al., 1999)

and University of Washington Lip-Philtrum Guide 1 were used for this Danish population.

Cognitive Function.—Child intelligence was assessed using the Wechsler Preschool and

Primary Scale of Intelligence-Revised (WPPSI-R) (Wechsler, 1990) covering the age span 3

to 7 years. The WPPSI-R includes 5 verbal and 5 performance subtests that are used to

calculate an overall verbal intelligence quotient (VIQ), overall performance IQ (PIQ), and

full-scale IQ (FSIQ). In this test battery, only 3 of the verbal (arithmetic, information, and

vocabulary) and 3 of the performance (block design, geometric design, and object assembly)

subtests were carried out to facilitate the child’s cooperation throughout the testing. Standard

procedures were used to prorate scores from the shortened test.

Child attention was assessed with the Test of Everyday Attention for Children at Five

(TEACh-5; Underbjerg et al., 2012, 2013) covering the age span 5 years to 5 years and 3

months. For this study, 2 subtests assessing selective attention (“Great Balloon Hunt” and

“Hide and Seek II”) and 2 subtests assessing sustained attention (“Barking” and “Draw a

line”) were used. Each subtest score was standardized to a mean of 0 and a SD of 1. To

calculate composite scores for overall, selective, and sustained attention, the means of the

respective standardized subtest scores for each individual were calculated and restandardized

to a mean of 0 and SD of 1.

Executive function was assessed using the Behavior Rating Inventory of Executive Function

(BRIEF) questionnaire (Gioia et al., 2000) covering the age span 5 to 18 years. The

questionnaire consists of 2 versions, 1 for parents and 1 for teachers. The parent version was

used for these analyses because of higher participation. Each questionnaire evaluates 8

domains of executive functioning and forms the Global Executive Composite (GEC). Three

of the 8 domains form the Behavioral Regulation Index (BRI), and 5 of the domains form



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the Metacognition Index (MI). Since the 8 domains do not follow a normal distribution, we

performed a normalizing t-score transformation to standardize each domain to a mean of 50

and SD of 10. To compute the GEC, BRI, and MI, the means of the respective domains for

each individual were calculated and restandardized to a mean of 50 and SD of 10. For all

BRIEF scores, a higher score indicates more executive function difficulties.

Covariates

Factors demonstrated in previous research to influence child neurodevelopment were

selected as covariates. The following covariates were obtained in the prenatal interview and

subsequently coded as follows: parity (0, 1, ≥2); prenatal smoking (yes/no); and maternal

prepregnancy body mass index (BMI) (weight in kg/[height in m]2). At the time of the 5-

year follow-up, the following variables were recorded: maternal marital status (single at

either the prenatal interview or follow-up/with partner at both times) and parental education

in years (total duration of attained education averaged for both parents or maternal only if

information on the father was missing). Additional information on collection of covariate

information is provided elsewhere (Kesmodel, 2012; Kesmodel et al., 2010).

Maternal age was obtained from the unique Danish personal identification number, as were

sex and age of the child. Birthweight in grams, head circumference, and gestational age in

days were obtained from the Danish Medical Birth Registry (Bliddal et al., 2018).

Data Analysis

Descriptive statistics (i.e., means, SDs, and proportions) were used to profile the

sociodemographics of the study population, the maternal drinking patterns, and the

magnitude of expression of the FAS facial features and phenotype. Logistic regression was

used to document the odds of presenting with the FAS/PFAS facial phenotype (Face Rank 3

or 4), short PFLs (ABC-Score = C, 2 or more SDs below the mean), smooth philtrum (Rank

4 or 5), or thin upper lip (Rank 4 or 5) relative to 4 different patterns of prenatal alcohol

exposure: (i) average number of drinks/week during pregnancy (0, 1 to 4, ≥5), (ii) binge

drinking (yes/no), (iii) number of binge drinking episodes (0, 1, 2 ≥ 3), and (iv) gestational

timing of the single binge drinking episode (no binge, weeks 1 to 2, weeks 3 to 4, weeks 5+;

multiple episodes). Odds ratios were adjusted for predefined covariates (parity; prenatal

smoking; maternal prepregnancy BMI; maternal marital status; parental education in years;

maternal age at the birth of the index child; sex and age of the child).

Not all photographs were of sufficient quality (e.g., facial expression, rotation, and focus) to

generate accurate measures of all 3 facial features. As a result, participants were divided into

2 groups. Group A (N = 366) consisted of children whose photographs were of sufficient

quality to measure all 3 facial features. Group B (N = 670) consisted of children whose

photographs were of sufficient quality to measure 1 to all 3 of the facial features. Group A is

a subset of Group B. Group B was used for analyses focused on the individual facial

features. Group A was used for analyses focused on the overall facial phenotype.

All analyses were conducted in SAS and Stata 12 (StataCorp LP, College Station, TX, USA)

and weighted by sampling probabilities. Statistical tests were 2-sided and deemed significant

at the 5% level. Estimates are accompanied by 95% confidence intervals.



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RESULTS

Sample Characteristics

Although the 2 subsets, Group A and Group B, were not randomly selected from the 1,628,

the sociodemographic profiles (Table 1) and maternal drinking patterns (Table 2) confirm

that both subgroups were highly reflective of one another and highly representative of the

1,628 participants from which they were drawn. Of the 366 women in Group A, 308 (84%)

reported, on average, low-to-moderate alcohol consumption with isolated episodes of binge

drinking, and 58 reported no alcohol consumption during pregnancy. Of the 670 women in

Group B, 561 (84%) reported, on average, low-to-moderate alcohol consumption with

isolated episodes of binge drinking, and 109 reported no alcohol consumption during

pregnancy (Table 2).

Occurrence of the FAS and PFAS Facial Phenotypes

Among the 366 participants with all 3 facial features measured, 308 had confirmed exposure

to alcohol. Nine of the 308 (2.9%) met the 4-Digit Code criteria for the moderate expression

of the FAS facial phenotype (Face Rank 3), and 1(0.3%) met the criteria for the severe

expression of the FAS facial phenotype (Face Rank 4) (Table 3). Measures of growth, CNS

structure and function, and maternal drinking patterns are presented in Table 4 to document

whether any of these 10 children met the diagnostic criteria for FAS or PFAS in accordance

with the FASD 4-Digit Code. All children were alcohol-exposed. Their mothers reported an

average intake of 0 to 7 drinks/wk before pregnancy, 0 to 2 drinks on average per week

during pregnancy, and a maximum of 1 binge episode during the first 20 weeks of

pregnancy. All children were born at term. Five of the 10 presented with growth, head

circumference, and/or IQ measures between 1 and 2 SDs below the mean. None of the

children presented with growth measures at or below the 10th percentile. One child

presented with a head circumference at the 10th percentile. In the absence of microcephaly

(head circumference less than or equal to third percentile), FAS and PFAS require evidence

of brain dysfunction. The level of brain dysfunction required for FAS or PFAS (CNS Rank

3) is defined by the 4-Digit Code as 3 or more domains of brain function, 2 or more SDs

below the mean based on a comprehensive assessment of language, memory, executive

function, cognition, motor, attention, and adaptation, using validated instruments

administered by clinical professionals (Astley, 2004). To confirm or rule out this level of

brain dysfunction, these assessments must be administered when a child is old enough

(typically >8 years) to engage in assessments of more complex, mature brain function

(Astley, 2004). None of the 10 children met the above criteria for brain dysfunction based on

the WPPSI-R IQ test. Thus, at 5 years of age, none of the 10 children met the 4-Digit Code

CNS criteria for FAS or PFAS, but all remain at risk for PFAS because CNS dysfunction

(CNS Rank 3) cannot be confirmed or ruled out at this young age.

Among the 304 children in which only 1 or 2 facial features could be measured, the full FAS

facial phenotype (Face Rank 4) could effectively be ruled out in 96% and the moderate

expression of FAS facial phenotype (Face Rank 3) could be ruled out in 77%. When

combined with the facial outcomes of the 366 children with all 3 facial features measured,



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the FAS/PFAS facial phenotypes (Face Ranks 3 to 4) could be ruled out in 96.7% of the 670

children.

Occurrence of the Individual FAS Facial Features

Among the 670 participants with 1, 2, or all 3 of the facial features measured, 4% presented

with PFLs 2 or more SDs below the mean (PFL ABC-Score = C), 11% presented with

moderately-to-completely smooth philtrums (Philtrum Ranks 4 and 5; ABC-Score = C), and

41% presented with moderately-to-severely thin upper lips (Lip Ranks 4 and 5; ABC-Score

= C; Table 3; Fig. 1). The prevalence of each FAS facial feature was nearly identical in the

smaller subset of 366 participants that had all 3 facial features measured.

Association Between FAS/PFAS Facial Features and Prenatal Alcohol Exposure

Table 5 shows the odds of presenting with the FAS/PFAS facial phenotypes (Face Rank 3 or

4) across different patterns of quantity, frequency, and timing of prenatal alcohol exposure.

Exposure to 1 to 4 drinks/wk on average during gestation was associated with a significant

8.5-fold increased odds for presenting with the FAS/PFAS facial phenotypes compared to

participants with no average drinks per week. Exposure to a single binge drinking episode

was associated with a significant 1.9-fold increased odds for the FAS/PFAS facial

phenotypes. When the timing of the single binge exposure was in gestational weeks 3 to 4,

participants were 2.5-fold more likely to present with the FAS/PFAS facial phenotypes than

participants with no binge exposure. Single binge exposures occurring before or after

gestational weeks 3 to 4 did not result in a significantly increased odds of the FAS/ PFAS

facial phenotypes.

Table 5 also presents the odds of presenting with each of the individual facial features of

FAS (short PFL: ≤−2 SDs, ABC-Score = C), smooth philtrum (Rank 4 or 5, ABC-Score =

C), and thin upper lip (Rank 4 or 5, ABC-Score = C) across the different patterns of prenatal

alcohol exposure.

PFL.—The odds of presenting with short PFLs (ABC-Score = C) increased significantly

from 1.8-fold to 3.7-fold as the average number of drinks per week during pregnancy

increased from 1 to 4 to ≥5. The odds of short PFLs increased significantly as the timing of

binge exposure occurred earlier in gestation. The odds were highest when binge(s) occurred

in weeks 1 to 2 and lowest when binge(s) occurred during or after gestational week 5,

although not statistically significant. The odds of short PFLs was highest with a single binge

exposure and significantly lower with 2 or more binge episodes.

Philtrum.—Odds of a smooth philtrum (ABC-Score = C) appeared to be more dependent

on the timing of binge exposure than the number of binge exposures. The odds were

significant and highest (1.3-fold higher) when binge drinking occurred in weeks 1 to 2. Odds

decreased linearly as binge drinking occurred later in gestation. Intake of 1 to 4 drinks/ wk

on average and 2 binge episodes in early pregnancy were associated with significantly lower

odds of a smooth philtrum.



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Lip.—Odds of upper lip thinness (ABC-Score = C) also appeared to be more dependent on

the timing of binge exposure rather than the number of binge exposures. Participants with 1

binge exposure were at significantly higher odds (Odds ratios [OR] 1.19) for thin upper lip

than participants with no binge exposures. When binge exposure occurred in weeks 3 to 4,

odds of a thin upper lip was greatest (OR 1.66). When binge exposure occurred in week 5 or

later, children were significantly less likely to present with a thin upper lip (OR 0.83).

Associations Between the Magnitude of Expression of the FAS Facial Phenotype and Other Diagnostic Features of FASD

Individuals with short PFLs (≤−2 SDs) had significantly lower mean FSIQ and PIQ scores

(5 to 7 points lower) than the reference group with normal PFLs (>−1 SD) (Table 6).

Individuals with smooth philtrums (Rank 4or 5) had significantly lower mean FSIQ and VIQ

scores (3 to 4 points lower) than individuals with deep philtrums (Rank 1 or 2). Individuals

with thin upper lip (Rank 4 or 5) had a significantly higher mean VIQ score (2.5 points

higher) than individuals with thicker upper lips (Ranks 1 and 2). When the 3 facial features

were assessed together, individuals with the Rank 3 or 4 FAS/PFAS facial phenotypes

presented with mean FSIQ and PIQ scores that were 4 to 7 points lower than the individuals

with normal facial phenotypes (Ranks 1 and 2). Although the magnitude and direction of

association were equivalent to those observed for the individual facial features, the contrasts

were not statistically significant. The smaller sample sizes resulted in insufficient power

(<80%) to identify the 4 to 7 point contrasts as statistically significant.

We found no significant or clinically relevant differences between children with different

facial phenotypes or different measures of individual facial features and executive function

and attention (data not presented).

Mean birthweight, birth length, and birth head circumference decreased significantly with

increasing magnitude of expression of the FAS facial phenotype (Face Ranks 1 to 4) among

the 366 participants in Group A (Fig. 2).

DISCUSSION

Summary

There were 3 core findings in this study with a sample of 670 children in which 109 had no

prenatal alcohol exposure and 561 had low-to-moderate exposure with isolated binge

episodes. First, 10 children presented with the FAS/PFAS facial phenotypes (Face Rank 3 or

4). All 10 were alcohol-exposed. None met the diagnostic criteria for FAS or PFAS at 5

years of age. All 10, however, remain at risk for PFAS because they were too young at age 5

years to engage in the battery of neuropsychological assessments required to confirm or rule

out brain dysfunction. Second, children exposed to 1 to 4 drinks/wk were 8.5-fold more

likely to present with the FAS/PFAS facial phenotypes (Rank 3 or 4) than children with no

prenatal alcohol exposure. Risk of the FAS/PFAS facial phenotypes was also significantly

increased (2.5-fold) among children with a single binge exposure in gestational weeks 3 to 4

compared to children with no binge exposures. And third, the magnitude of expression of the

FAS facial phenotype was significantly correlated with all other diagnostic features of FAS:



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growth deficiency, microcephaly, and measures of CNS dysfunction, even if measures of

these features were within the normal range in this sample.

A primary objective of this study was to determine whether adverse outcomes typically

observed among populations with high PAE could be found in a population with much lower

exposure. Since the facial features that define FAS/PFAS were measured using the same

software (Astley, 2016), personnel, and FASD diagnostic system (Astley, 2004) used to

measure facial features in the University of Washington FASDPN clinical population,

relevant comparisons can be made between the 2 populations. The FASDPN dataset includes

over 3,000 individuals with prenatal alcohol exposure who received an interdisciplinary

FASD diagnostic evaluation using the FASD 4-Digit Diagnostic Code (Astley, 2010). The

alcohol exposures reported in the current study population (83% reported no more than 1 to

8 drinks/wk and/or isolated binge episode [drinking categories 1a to 4c; Table 1]) were

considerably lower than the alcohol exposures reported in the FASDPN clinical population

(76% report greater than 1 to 8 drinks/wk; average exposure is 7 to 9 drinks per occasion, 4

to 5 d/wk) (Astley, 2010).

Prevalence of FAS Facial Features and Correlation with Prenatal Alcohol Exposure

In the current study population with low-to-moderate prenatal alcohol exposure, 3.2%

(10/308) presented with the FAS/PFAS facial phenotypes (Rank 3 or 4). All were exposed to

no more than 7 drinks/wk and no more than a single episode of binge drinking. In contrast, a

much higher proportion of individuals (19%) present with the FAS/PFAS facial phenotypes

in the FASDPN patient population (Astley, 2010). Although individuals in the FASDPN

patient population are, on average, highly exposed, 1 of every 14 diagnosed with FAS/PFAS

has a reported exposure of no more than 7 drinks/wk. This is similar to the 10 children with

the FAS/PFAS facial phenotypes in the current study. Although prenatal alcohol exposure

may have been underreported for these 1 in 14 cases, it is also possible that these children

are particularly vulnerable to lower levels of exposure. Future research may want to examine

this possibility. The outcomes in the current study suggest that lower exposures may, in fact,

be sufficient to produce the FAS/PFAS facial phenotypes in a small proportion of children.

Timing of exposure also appears to be important. Perhaps one of the most compelling

findings in the current study was a significant 2.5-fold increased odds of the FAS/PFAS

facial phenotypes among children with a single binge exposure in gestational weeks 3 to 4.

Gestational weeks 3 and 4 reflect the primitive streak and gastrulation stage of

embryogenesis—a critical period of induction of alcohol-induced craniofacial alterations

(Astley, 2013; Astley et al., 1999; Sulik, 1984).

FAS and PFAS require more than just the Rank 3 or 4 facial phenotype. Although 10

children in the current study presented with the Rank 3 or 4 FAS/PFAS facial phenotypes,

none met the diagnostic criteria for FAS or PFAS (in accordance with the 4-Digit Code) at

the young age of 5 years. FAS is defined by growth ≤10th percentile, a Rank 4 facial

phenotype, and microcephaly (less than or equal to third percentile) and/or brain dysfunction

(3 or more domains of brain function 2 or more SDs below the mean) (Astley, 2004). PFAS

is defined by normal growth, a Rank 3 or 4 facial phenotype, and microcephaly and/or brain

dysfunction (3 or more domains of brain function 2 or more SDs below the mean). Since no



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child presented with growth ≤10th percentile, no child met the criteria for FAS. In contrast,

all 10 children met the growth and facial criteria for PFAS. None of them presented with

microcephaly; therefore, CNS dysfunction would be required to meet the CNS criteria for

PFAS. Nevertheless, at 5 years of age, all were too young to participate in the battery of

assessments required to confirm or rule out CNS dysfunction. As documented in the

FASDPN clinical population, most children with FAS or PFAS do not present with severe

brain dysfunction until later in childhood. For example, among 87 children ≤5 years of age

at the time of their FAS/PFAS diagnosis at the FASDPN, only 24% met the criteria for

severe CNS dysfunction (3 or more domains of function 2 or more SDs below the mean).

Among 152 children >5 years of age at the time of their FAS/PFAS diagnosis, 84% met the

criteria for severe CNS dysfunction. In addition, recent research (Astley et al., 2016)

documents that 67 and 70% of young children with prenatal alcohol exposure that present

with the Rank 3 or 4 FAS facial phenotypes, respectively, will present with severe CNS

dysfunction (3 or more domains of brain function 2 or more SDs below the mean) when they

are old enough (>8 years of age) to engage in more sophisticated assessments of brain

function. Thus, if any of the 10 children with the Rank 3 or 4 FAS/PFAS facial phenotypes

present with brain dysfunction (3 or more domains of brain function 2 or more SDs below

the mean) later in childhood, they would meet the diagnostic criteria for PFAS.

Prenatal alcohol exposure was significantly correlated with the FAS facial phenotype and the

3 individual features that comprise the FAS facial phenotype. The strongest correlations with

alcohol (ORs of 1.9 to 8.5) were observed when the 3 features appeared together to produce

the Rank 3 or 4 FAS/PFAS facial phenotypes (Table 5). Since the Rank 4 FAS facial

phenotype is confirmed to be highly specific to prenatal alcohol exposure (Astley, 2013;

Astley and Clarren, 1996), it is highly likely that the FAS/PFAS facial phenotypes observed

in these 10 children were caused by their prenatal alcohol exposure. Weaker, but statistically

significant, correlations (ORs of 1.2 to 3.7) were observed between prenatal alcohol

exposure and each individual FAS facial feature. This would be expected since alcohol is not

the only factor influencing the length of a palpebral fissure, the depth of a philtrum, or the

thickness of an upper lip. Perhaps one of the strongest factors other than alcohol influencing

the physical presentation of these 3 facial features is familial genetics. A unique strength of

the current study was the opportunity to measure the birth mothers’ facial features. Among

the 10 children who presented with the Rank 3 or 4 FAS facial phenotypes, all of their birth

mothers presented with normal facial phenotypes (Face Ranks 1 and 2).

Correlations Between the FAS Facial Phenotype and Growth Deficiency, Microcephaly, and CNS Dysfunction

The correlations between face, growth, and CNS abnormalities observed in the current study

(Fig. 2) are nearly identical to those documented in the FASDPN clinical population (figures

8 and 9 in Astley, 2013). This study extends understanding of these correlations to a

population of children with low-to-moderate prenatal alcohol exposure.

Strengths

The sample of women and children used for this study form part of a well-described,

prospective cohort (Kesmodel et al., 2010; Olsen et al., 2001). While information bias is



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always a potential problem in observational studies (Kesmodel, 2018), the risk of

information bias was minimized. Information on alcohol drinking patterns was collected

directly from the birth mothers during pregnancy using validated instruments (Kesmodel,

2001; Kesmodel and Olsen, 2001), and all facial measures were performed by the inventor

of the software system (Astley, 2016) used in this paper, thereby eliminating any

interobserver variability and reducing the likelihood of measurement error. Further, facial

measurements were taken blind to the child’s exposure history. Because of the detailed

information available on all participants, confounding could be addressed by adjusting for a

priori selected potential confounders (Howards, 2018), following the same criteria as

previous papers based on this cohort (Kesmodel et al., 2012). Also, it has previously been

shown that despite selection problems in the DNBC, the external validity of measures of

association seems to be good (Nohr and Liew, 2018).

Weaknesses

The DNBC represents only approximately 30% of all Danish pregnant women and hence is

not a representative sample (Olsen et al., 2001). Further, the LDPS sample is a stratified

sample within the DNBC (Kesmodel et al., 2010), making the current sample even less

representative of the background population. While such selection may make the sample less

suitable for firm statements about the overall prevalence of specific traits, inferences based

on measures of association have been shown to be valid within the cohort (Nohr and Liew,

2018). Finally, since only 10 children presented with the Rank 3 to 4 facial phenotypes, the

representativeness of this small group may be limited, but the statistical power was sufficient

to identify significant associations with level and timing of prenatal alcohol exposure.

CONCLUSION

In conclusion, we found that approximately 3% (10/308) of the children whose mothers

reported low-to-moderate alcohol intake, not usually associated with the full FAS, met the

criteria for moderate-to-severe expression of the FAS facial phenotypes, Face Ranks 3 to 4.

None met the diagnostic criteria for FAS or PFAS at 5 years of age. However, all 10 remain

at risk for PFAS because they were too young at age 5 years to engage in the battery of

neuropsychological assessments required to confirm or rule out severe brain dysfunction.

The risk of FAS/PFAS facial phenotypes (Ranks 3 to 4) was significantly increased among

both women with average alcohol intake of 1 to 4 drinks/wk and women with isolated

episodes of binge drinking, particularly during gestational weeks 3 to 4. These findings

suggest that low-to-moderate levels of prenatal alcohol exposure or isolated binge exposures

may place some fetuses at risk for FAS, PFAS, or other FASDs. Thus, conservative advice is

still for women to abstain from alcohol consumption during pregnancy.

ACKNOWLEDGMENTS

Primary support for this study was provided by the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA. The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the DNBC. The cohort was furthermore a result of a major grant from this Foundation. Additional support for the DNBC was obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation. The authors would like to thank all the participants for their time and efforts.



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APPENDIX: DETAILED PROCEDURES FOR TAKING AND SELECTING

PHOTOGRAPHS FOR FACIAL CODING:

To examine the association between facial features used to diagnose FAS/PFAS and low-to-

moderate prenatal alcohol exposure, digital photographs were obtained, selected, and

categorized for FAS/PFAS criteria according to the FASD 4-Digit Code (Astley, 2004).

Details of these procedures are described in this appendix.

Taking Digital Photographs

Each participant had a standardized frontal, oblique, and lateral digital facial photograph

taken in accordance with the FAS Facial Photographic Analysis Software instructions

(Astley, 2016). Briefly, the child had a relaxed facial expression (no smile, lips gently

closed, eyes fully open with no eyeglasses), and the digital images had proper rotation,

exposure, and focus. A 19.05-mm-diameter round paper sticker was placed between the

participant’s eyebrows as an internal measure of scale. Photographs were taken according to

the protocol outlined in Astley (2016), and lead psychologists received in-person training on

how to take the photographs by SA.

Selection of Photographs for Facial Coding

Resources and photograph quality did not permit the complete analysis of all 1,628

participants’ photographs. Thus, a stepwise approach was used to identify those children

with clear or suggestive indication of facial dysmorphia for further measurement. The goal

was to identify all individuals that presented with 1, 2, or all 3 of the FAS facial features as

defined above. The photographs were measured by authors AG and SA in a 2-step process,

masked to the participant’s alcohol exposure.

• Step 1: AG measured the PFLs and lip circularities of all 1,628 participants

regardless of the quality of the feature in the photograph (e.g., the eyes were not

fully open, the child was smiling, or the sticker curled). If the eyes are not fully

open, the child is smiling, or the sticker is slightly curled, the direction of error

will always be in 1 direction; the PFLs will be shorter, the lip thinner, and the

philtrum smoother than they truly are. SA reviewed the subset from Step 1 that

appeared to have short PFLs ≤−1.5 SDs and/or thin upper lips (lip circularities

≥70) and identified the subset that had sufficient image quality to ensure the PFL

and lip circularity measures could be accurately measured. SA then remeasured

the PFLs and lip circularities of this subset to ensure the highest level of

consistency and accuracy across all facial measures.

• Step 2: SA also reviewed the philtrum of all 1,628 participants and ranked only

the subset with philtrum images of sufficient image quality and met criteria for

Rank 4 or 5.



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Final FAS/PFAS Determination

For all viable photographs, whenever a participant was identified as having at least 1 facial

feature in the FAS range, the other 2 facial features were also measured if the quality of the

image was sufficient. Once measurement of the 3 facial features was complete, the software

generated a 4-Digit Code Facial ABC-Score and Face Rank (Fig. 1). For example, if a child

presented with PFLs 2.6 SDs below the mean, a Rank 3 philtrum, and a Rank 2 upper lip,

they would receive a Facial ABC-Score of CBA and a Face Rank of 2 (mild). If 1 or 2 of the

3 facial features could not be measured, an “X” was placed in the ABC-Score to signify its

absence (e.g., the ABC-Score XCA signifies that the PFL could not be measured, but the

philtrum was a “C” and the lip was an “A” [see Fig. 1B]). A Face Rank could not be

generated if 1 or 2 of the 3 features could not be measured, but Facial ABC-Scores with 1 or

2 missing features could be used to accurately rule out 1 or more of Face Ranks 1 to 4. For

example, if a Facial ABC-Score was XXA, Face Ranks 3 and 4 can be accurately ruled out

despite not knowing the outcome of the PFL or philtrum, because neither can include a

feature with a Rank A.

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Fig. 1. (A) University of Washington Lip-Philtrum Guide 1 used to rank lip thinness and philtrum

smoothness on 5-point Likert scales. (B) The face tables on the backside of the Lip-Philtrum

Guide outline how the magnitude of expression of the FAS facial phenotype is ranked on a

4-point scale (Rank 1: normal; Rank 2: mild; Rank 3: moderate; and Rank 4: severe) (Astley,

2004). Copyright Susan Astley Hemingway. Reprinted by permission.



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Fig. 2. Mean birthweight, birth length, and birth head circumference decreased significantly with

increasing magnitude of expression of the FAS facial phenotype (Face Ranks: 1, normal; 2,

mild; 3, moderate; and 4, severe) among the 366 participants in Group A. Error bars reflect

95% CIs. One-way ANOVA test for linear trend p-values: birth length 0.04, and birth-weight

and head circumference 0.001.



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Tab

le 1

.

Sam

ple

Cha

ract

eris

tics

of th

e C

urre

nt S

tudy

Pop

ulat

ions

and

the

Ori

gina

l LD

PS P

opul

atio

n fr

om W

hich

The

y W

ere

Dra

wn

LD

PS

2012

stu

dy p

arti

cipa

nts

Mot

her

and

child

pai

rs f

rom

alc

ohol

sam

plin

g ca

tego

ries

1 t

o 5

Cur

rent

201

8 st

udy

part

icip

ants

Chi

ldre

n fr

om t

he L

DP

S w

ith

Gro

up A

All

3 fa

cial

fea

ture

s m

easu

red

Gro

up B

1 t

o 3

faci

al f

eatu

res

mea

sure

d

Sam

ple

char

acte

rist

ics

n

1,62

836

667

0

Sa

mpl

ing

frac

tion

(med

ian,

10t

h/90

th p

erce

ntile

)9.

7 (1

.5/4

9.6)

9.7

(1.5

/49.

6)9.

7 (1

.2/4

9.6)

T

imin

g of

inte

rvie

w, g

esta

tiona

l wee

k (m

edia

n, 1

0th/

90th

per

cent

ile)

17 (

13/2

4)17

(13

/23)

17 (

13/2

3)

Fam

ily c

hara

cter

istic

s

M

ater

nal a

ge, y

ears

(m

ean

± S

D)

Pari

ty30

.9 ±

4.4

30.9

± 4

.330

.9 ±

4.3

0 (%

)50

.148

.949

.1

1 (%

)32

.231

.732

.1

≥2 (

%)

17.8

19.4

18.8

M

ater

nal B

MI

(bef

ore

preg

nanc

y), k

g/m

2 (m

edia

n, 1

0th/

90th

per

cent

ile)

22.6

(19

.6/2

8.7)

22.5

(19

.7/2

9.3)

22.6

(19

.6/2

9.1)

M

ater

nal m

arita

l sta

tus:

sin

gle

(%)

12.1

12.0

11.0

Pa

rent

al e

duca

tion,

yea

rs (

med

ian,

10t

h/90

th p

erce

ntile

)13

.0 (

11.0

/16.

0)12

.5 (

11.0

/16.

0)13

.0 (

11.0

/16.

0)

Fa

mily

hom

e in

dex:

sub

optim

al (

%)

18.7

20.8

18.6

M

ater

nal I

Q (

mea

n ±

SD

)10

0.0

± 1

5.0

100

± 1

4.8

M

ater

nal s

mok

ing

duri

ng p

regn

ancy

(%

)31

.433

.932

.2

Pa

rent

al p

ostn

atal

sm

okin

g (%

)31

.933

.331

.1

M

ater

nal b

inge

dri

nkin

g in

pre

gnan

cy (

%)

69.6

70.8

67.6

M

edia

n nu

mbe

r of

dri

nks

per

wee

k du

ring

pre

gnan

cy (

med

ian,

10t

h/90

th

perc

entil

e)0.

5 (0

/5)

0.5

(0/5

)0,

5 (0

/5)

Chi

ld c

hara

cter

istic

s

M

ale

sex

(%)

52.0

46.5

48.5

A

ge a

t tes

ting,

yea

rs (

med

ian,

10t

h/90

th p

erce

ntile

)5.

2 (5

.1/5

.3)

5.2

(5.1

/5.3

)5.

2 (5

.1/5

.3)

B

irth

wei

ght,

gram

s (m

ean

± S

D)

3601

.9 ±

516

.13,

600

± 5

07.3

3613

.6 ±

521

.4

G

esta

tiona

l age

, day

s (m

edia

n, 1

0th/

90th

per

cent

ile)

281

(267

/293

)28

1 (2

67/2

93)

282

(269

/293

)

M

edic

al c

ondi

tion

or m

edic

atio

n (%

)3.

31.

62.

4

Im

pair

ed h

eari

ng a

bilit

ies

(%)

4.7

4.4

4.8

Im

pair

ed v

isio

n ab

ilitie

s (%

)2.

92.

52.

7


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Tab

le 2

.

Dis

trib

utio

n of

Mat

erna

l Dri

nkin

g Pa

ttern

s in

the

Ori

gina

l LD

PS 2

012

Stud

y an

d th

e C

urre

nt 2

018

Stud

y

Ave

rage

sta

ndar

d dr

inks

per

wee

kB

inge

a dri

nkin

gL

DP

S201

2bC

urre

nt 2

018

Fac

ial S

tudy

Ges

tati

onal

wee

ksP

arti

cipa

nts

Gro

up A

All

3 fa

cial

fea

ture

s m

easu

red

Gro

up B

1 t

o 3

faci

al f

eatu

res

mea

sure

d

Dur

ing

preg

nanc

y1

to 2

3 to

45

to 8

≥9N

= 1

,622

NN

=36

6 N

(%

of

LD

PS)

N =

670

N (

%of

LD

PS)

0N

oN

oN

oN

o25

758

(23

)10

9 (4

2)

0Y

esN

oN

oN

o11

328

(25

)47

(42

)

0N

oY

esN

oN

o10

425

(24

)42

(40

)

0N

oN

oY

esN

o10

924

(22

)55

(50

)

0N

oN

oN

oY

es94

21 (

22)

38 (

40)

Tota

l 677

Tota

l 156

(23

)To

tal 2

91 (

43)

1 to

4N

oN

oN

oN

o15

530

(19

)72

(46

)

1 to

4Y

esN

oN

oN

o11

330

(27

)43

(38

)

1 to

4N

oY

esN

oN

o12

023

(19

)43

(36

)

1 to

4N

oN

oY

esN

o93

28 (

30)

45 (

48)

1 to

4N

oN

oN

oY

es11

421

(18

)39

(34

)

Tota

l 595

Tota

l 132

(22

)To

tal 2

42 (

41)

0Y

es in

at l

east

281

21 (

26)

33 (

41)

1 to

8Y

es in

at l

east

282

15 (

18)

28 (

34)

1 to

3 to

≥5To

tal 1

63To

tal 3

6 (2

2)To

tal 6

1 (3

7)

24

5 to

8N

oN

oN

o79

17 (

22)

35 (

44)

5 to

8Y

esN

oN

o11

1 (9

)1

(9)

5 to

8N

oY

esN

o37

7 (1

9)15

(41

)

5 to

8N

oN

oY

es40

12 (

30)

18 (

45)

≥9N

oN

oN

o15

4 (2

7)5

(33)

≥9Y

es in

at l

east

25

1 (2

0)2

(40)

Tota

l 187

Tota

l 42

(22)

Tota

l 76

(41)

No.

of

bing

e dr

inki

ng e

piso

des

duri

ng p

regn

ancy

049

510

7 (2

2)21

7 (4

4)

178

318

2 (2

3)31

2 (4

0)


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Ave

rage

sta

ndar

d dr

inks

per

wee

kB

inge

a dri

nkin

gL

DP

S201

2bC

urre

nt 2

018

Fac

ial S

tudy

Ges

tati

onal

wee

ksP

arti

cipa

nts

Gro

up A

All

3 fa

cial

fea

ture

s m

easu

red

Gro

up B

1 t

o 3

faci

al f

eatu

res

mea

sure

d

Dur

ing

preg

nanc

y1

to 2

3 to

45

to 8

≥9N

= 1

,622

NN

=36

6 N

(%

of

LD

PS)

N =

670

N (

%of

LD

PS)

222

547

(21

)95

(42

)

3 to

12

114

30 (

26)

46 (

40)

a Def

ined

as

an in

take

of

5 or

mor

e st

anda

rd d

rink

s on

one

occ

asio

n.

b Lif

esty

le D

urin

g Pr

egna

ncy

Stud

y 20

12.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Tab

le 3

.

Dis

trib

utio

n of

the

FAS

Faci

al F

eatu

res

in th

e 2

Stud

y Po

pula

tions

Gro

up A

All

3 fa

cial

fea

ture

s m

easu

red

N (

valid

%)

Gro

up B

1 t

o 3

faci

al f

eatu

res

mea

sure

d N

(va

lid %

)

Num

ber

of f

acia

l fea

ture

s m

easu

reda

Tota

l N =

366

Tota

l N =

670

O

nly

10

(0%

)10

2 (1

5%)

2

of th

e 3

0 (0

%)

202

(30%

)

A

ll 3

366

(100

%)

366

(55%

)

FAS

face

ran

k

N

orm

al: R

ank

117

2 (4

7%)

172

M

ild: R

ank

218

4 (5

0%)

184

M

oder

ate:

Ran

k39

(2%

)9

Se

vere

: Ran

k41

(< 1

%)

1

A

mon

g th

e 30

4 w

ith o

nly

1 or

2 f

eatu

res

mea

sure

dbTo

tal N

= 3

04

Ran

k 1

rule

d ou

tN

/A12

(4%

)

Ran

k 4

rule

d ou

tN

/A38

(12

%)

Ran

ks 1

and

4 r

uled

out

N/A

20 (

7%)

Ran

ks 3

and

4 r

uled

out

N/A

211

(69%

)

Ran

ks 1

, 3, a

nd 4

rul

ed o

utN

/A23

(8%

)

PFL

Tota

l N =

366

Tota

l N =

491

A

BC

-Sco

rec

A(>

−1

SD)

298

(81%

)41

1 (8

4%)

B (

>−

2 SD

s &

≤−

1 SD

)50

(14

%)

58 (

12%

)

C (

≤−2

SDs)

18 (

5%)

22 (

4%)

Philt

rum

sm

ooth

ness

A

BC

-Sco

rec

Tota

l N =

366

Tota

l N =

648

A (

Ran

k 1

or 2

)15

2 (4

1%)

261

(40%

)

B (

Ran

k 3)

168

(46%

)31

4 (4

9%)

C (

Ran

k 4

or 5

)46

(13

%)

73 (

11%

)

5-

Poin

t Ran

kcTo

tal N

= 3

66To

tal N

= 6

48

1 (d

eepl

y gr

oove

d)30

(8%

)54

(8%

)


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Gro

up A

All

3 fa

cial

fea

ture

s m

easu

red

N (

valid

%)

Gro

up B

1 t

o 3

faci

al f

eatu

res

mea

sure

d N

(va

lid %

)

2 (m

oder

atel

y gr

oove

d)12

2 (3

3%)

207

(32%

)

3 (n

orm

al g

roov

e)16

8 (4

6%)

314

(48%

)

4 (m

oder

atel

y sm

ooth

)42

(11

%)

69 (

11%

)

5 (v

ery

smoo

th)

4 (1

%)

4 (1

%)

Upp

er li

p th

inne

ss

A

BC

-Sco

rec

Tota

l N =

366

Tota

l N =

465

A (

Ran

k 1

or 2

)75

(20

%)

102

(22%

)

B (

Ran

k 3)

130

(36%

)17

4 (3

7%)

C (

Ran

k 4

or 5

)16

1 (4

4%)

189

(41%

)

5-

Poin

t Ran

kcTo

tal N

= 3

66To

tal N

= 4

65

1 (v

ery

thic

k)8

(2%

)11

(2%

)

2 (m

oder

atel

y th

ick)

67 (

18%

)91

(20

%)

3 (n

orm

al th

ickn

ess)

130

(36%

)17

4 (3

7%)

4 (m

oder

atel

y th

in)

135

(37%

)16

1 (3

5%)

5 (v

ery

thin

)26

(7%

)28

(6%

)

a The

qua

lity

of a

chi

ld’s

pho

tose

t did

not

alw

ays

allo

w a

ll 3

faci

al f

eatu

res

to b

e m

easu

red.

b Eve

n th

ough

onl

y 1

or 2

fac

ial f

eatu

res

coul

d be

mea

sure

d, th

e ou

tcom

e of

thos

e fe

atur

es a

llow

ed 1

or

mor

e Fa

ce R

anks

to b

e ru

led

out.

c See

Fig.

1.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Tab

le 4

.

Cha

ract

eris

tics

of th

e 10

Chi

ldre

nWith

Ran

k 3

or R

ank

4 FA

S Fa

cial

Phe

noty

pes.

Gro

wth

a and

Neu

rops

ycho

logi

calb O

utco

mes

Pro

vide

d in

Ter

ms

of D

evia

tion

From

the

Mea

n in

Sta

ndar

d D

evia

tions

Usi

ng

Stan

dard

ized

Nor

ms

Chi

ldM

ater

nal

Chi

ld

Ave

rage

alc

ohol

inta

ke d

rink

s pe

r w

eek

Alc

ohol

bin

ge e

piso

des

At

birt

hA

t 5

year

s of

age

Fac

e R

ank

Sex

Pla

nned

pr

egna

ncy

Bef

ore

preg

nanc

yD

urin

g pr

egna

ncy

Num

ber

Tim

ing:

ges

tati

onal

w

eeks

Ges

tati

onal

age

cB

irth

wei

ght

Len

gth

at b

irth

Hea

d ci

rcum

fere

nce

at

birt

hW

eigh

t at

age

5H

eigh

t at

age

5H

ead

circ

umfe

renc

e at

age

5IQ

at

age

5T

EA

Ch

(ove

rall

atte

ntio

n, m

ean)

BR

IEF

(G

EC

mea

n)

3M

ale

Yes

0.0

0.0

19+

39N

NN

NN

NN

NN

3M

ale

Yes

0.0

0.0

19+

40N

NN

NN

NN

N−

1.9

SD; −

1 SD

3M

ale

Yes

0.5

0.5

041

NN

NN

NN

1 SD

; 1.9

SD

NN

3Fe

mal

eN

o0.

50.

51

1 to

240

−1.

9 SD

; −1

SDN

NN

NN

N−

1.9

SD; −

1 SD

N

3M

ale

Yes

3.0

0.0

13

to 4

40N

NN

NN

−1.

9 SD

; −1

SDN

1 SD

; 1.9

SD

N

3Fe

mal

eY

es3.

02.

00

41N

NN

NN

NN

NN

3Fe

mal

eY

es4.

00.

51

3 to

439

−1.

9 SD

; −1

SDN

NN

NN

−1.

9 SD

; −1

SDN

−1.

9 SD

; −1

SD

3M

ale

No

6.0

0.0

15

to 8

39N

NN

1 SD

; 1.9

SD

1 SD

; 1.9

SD

NN

NN

3M

ale

Yes

7.0

0.0

11

to 2

40N

NN

−1.

9 SD

; −1

SDN

−1.

9 SD

; −1

SDN

−1.

9 SD

; −1

SDN

4Fe

mal

eY

es1.

00.

51

3 to

439

−1.

9 SD

; −1

SDN

N1

SD; 1

.9 S

D1

SD; 1

.9 S

DN

NN

N

a Ant

hrop

omet

ric

mea

sure

s or

igin

ally

rep

orte

d in

gra

ms

(bir

thw

eigh

t), k

g (w

eigh

t at a

ge 5

yea

rs),

or

cm (

leng

th a

t bir

th, h

eigh

t at a

ge 5

yea

rs, h

ead

circ

umfe

renc

e at

bir

th a

nd a

t age

5 y

ears

). P

rese

nted

as

devi

atio

ns f

rom

the

mea

n in

SD

(D

anis

h st

anda

rd g

row

th c

urve

s) in

ord

er

to a

void

iden

tific

atio

n of

indi

vidu

als.

b FSIQ

mea

sure

d w

ith W

PPSI

-R o

n st

anda

rd I

Q-s

cale

(m

ean

of 1

00, S

D =

15)

. Atte

ntio

n m

easu

red

with

TE

AC

h-5

(Tes

t of

Eve

ryda

y A

ttent

ion

for

Chi

ldre

n at

Fiv

e). E

xecu

tive

func

tion

mea

sure

d w

ith B

RIE

F (B

ehav

ior

Rat

ing

Inve

ntor

y of

Exe

cutiv

e Fu

nctio

n). P

rese

nted

as

devi

atio

ns f

rom

the

mea

n: N

= −

1 SD

to +

1 SD

fro

m p

opul

atio

n m

eans

to a

void

iden

tific

atio

n of

indi

vidu

als.

c Cal

cula

ted

in d

ays

and

conv

erte

d to

com

plet

ed w

eeks

as

pres

enta

tion

in d

ays

pote

ntia

lly a

llow

s fo

r id

entif

icat

ion

of in

divi

dual

s.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Tab

le 5

.

Odd

s R

atio

sa for

Dys

mor

phic

Fac

ial F

eatu

res

Am

ong

the

366

Chi

ldre

n fr

om G

RO

UP

AW

ith a

ll 3

Faci

al F

eatu

res

Mea

sure

d an

d th

e 67

0 C

hild

ren

From

Gro

up B

With

1 to

3 F

acia

l Fea

ture

s M

easu

red

in R

elat

ion

to P

atte

rn o

f M

ater

nal A

lcoh

ol C

onsu

mpt

ion

Dur

ing

Preg

nanc

y

Alc

ohol

pat

tern

Fac

e ra

nks

3 to

4 v

ersu

s 1

to 2

N =

10

vers

us n

= 3

56F

rom

Gro

up A

: N

= 3

66O

R (

95%

CI)

PF

L A

BC

-Sco

resb

C v

ersu

s A

BN

= 2

2 ve

rsus

N =

469

Fro

m G

roup

B:

N =

670

OR

(95

% C

I)

Phi

ltru

m A

BC

-Sco

resb

C v

ersu

s A

BN

= 7

3 ve

rsus

N =

575

Fro

m G

roup

B:

N =

670

OR

(95

% C

I)

Upp

er li

p A

BC

-Sco

resb

C v

ersu

s A

BN

= 1

89 v

ersu

s N

= 2

76F

rom

Gro

up B

: N

= 6

70O

R (

95%

CI)

Ave

rage

num

ber

of d

rink

s pe

r w

eek

duri

ng p

regn

ancy

0

Ref

eren

ceR

efer

ence

Ref

eren

ceR

efer

ence

1

to 4

8.50

(6.

03 to

12.

0)1.

76 (

1.42

to 2

.16)

0.87

(0.

79 to

0.9

6)0.

97 (

0.90

to 1

.05)

≥5

No

rank

3 to

4 fa

ces

in th

is c

ateg

ory

3.71

(2.

15 to

6.4

0)0.

76 (

0.47

to 1

.24)

1.16

(0.

85 to

1.5

8)

p-

Val

uec

<0.

001

<0.

001

0.01

0.46

Bin

ge d

rink

ing

in p

regn

ancy

N

oR

efer

ence

dR

efer

ence

Ref

eren

ceR

efer

ence

Y

es1.

36 (

1.03

to 1

.78)

0.85

(0.

67 to

1.0

8)0.

92 (

0.82

to 1

.03)

1.08

(0.

99 to

1.1

8)

p-

Val

ue0.

030.

190.

150.

07

Num

ber

of b

inge

dri

nkin

g ep

isod

es in

pre

gnan

cy

0

Ref

eren

ceR

efer

ence

cR

efer

ence

Ref

eren

ce

1

1.94

(1.

48 to

2.5

4)1.

20 (

0.94

to 1

.54)

1.00

(0.

87 to

1.1

4)1.

19(1

.08

to 1

.31)

2

No

rank

3 to

4 fa

ces

in th

is c

ateg

ory

0.11

(0.

03 to

0.3

5)0.

71 (

0.57

to 0

.89)

0.86

(0.

74 to

0.9

9)

≥3

No

rank

3 to

4 fa

ces

in th

is c

ateg

ory

0.44

(0.

21 to

0.9

6)0.

96 (

0.70

to 1

.31)

1.08

(0.

87 to

1.3

5)

p-

Val

ue<

0.00

1<

0.00

10.

020.

93

Tim

ing

of b

inge

dri

nkin

g ep

isod

es in

pre

gnan

cy (

gest

atio

nal w

eek)

N

o bi

nge

Ref

eren

ceR

efer

ence

Ref

eren

ceR

efer

ence

W

eeks

1 to

2 o

nly

1.46

(0.

90 to

2.3

5)1.

13 (

0.76

to 1

.69)

1.32

(1.

08 to

1.6

2)1.

12 (

0.95

to 1

.31)

W

eeks

3 to

4 o

nly

2.47

(1.

79 to

3.4

1)1.

10 (

0.78

to 1

.56)

0.91

(0.

76 to

1.0

8)1.

66 (

1.46

to 1

.90)

W

eek

>5

only

0.80

(0.

43 to

1.4

9)0.

99 (

0.66

to 1

.48)

0.87

(0.

69 to

1.0

8)0.

83 (

0.71

to 0

.98)

M

ultip

le e

piso

des

No

rank

3 to

4 fa

ces

in th

is c

ateg

ory

No

rank

C P

FLs

in th

is c

ateg

ory

0.79

(0.

62 to

1.0

1)1.

05 (

0.89

to 1

.24)

p-

Val

ue<

0.00

1<

0.00

10.

007

<0.

001

a OR

adj

uste

d fo

r so

ciod

emog

raph

ic a

nd s

ampl

ing

fact

ors.

95%

conf

iden

ce in

terv

als

that

do

not s

pan

1.0

are

stat

istic

ally

sig

nifi

cant

at p

< 0

.05.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript

Schiøler Kesmodel et al. b Fa

cial

AB

C-S

core

s fr

om th

e FA

SD 4

-Dig

it C

ode

are

defi

ned

in F

ig. 1

.

c p-V

alue

for

the

hypo

thes

is o

f no

dif

fere

nce

in f

acia

l fet

aure

s ac

ross

leve

ls o

f al

coho

l int

ake.

d The

ref

eren

ce g

roup

s ha

ve z

ero

expo

sure

onl

y fo

r th

e ty

pe o

f ex

posu

re p

atte

rn b

eing

ass

esse

d, b

ut h

ave

the

full

rang

e of

exp

osur

e ba

sed

on th

e ot

her

patte

rns.

For

exa

mpl

e, th

is r

efer

ence

gro

up o

f 10

9 pa

rtic

ipan

ts h

as z

ero

bing

e ep

isod

es o

f ex

posu

re, b

ut 3

0 (2

8%)

wer

e ex

pose

d to

an

aver

age

of 1

to 4

dri

nks/

wk

duri

ng p

regn

ancy

and

21

(19%

) w

ere

expo

sed

to a

n av

erag

e of

5 o

r m

ore

drin

ks/w

k du

ring

pr

egna

ncy.


Author M

anuscriptA

uthor Manuscript

Author M

anuscriptA

uthor Manuscript


Tab

le 6

.

Ass

ocia

tion

Bet

wee

n Fa

cial

Fea

ture

s an

d C

hild

IQ

a

Inte

llige

nce

Ful

l-sc

ale

IQ (

stan

dard

sco

re)

Per

form

ance

IQ

(st

anda

rd s

core

)V

erba

l IQ

(st

anda

rd s

core

)

Mea

nM

ean

diff

eren

ce95

% C

Ip-

Val

ueM

ean

Mea

n di

ffer

ence

95%

CI

p-V

alue

Mea

nM

ean

diff

eren

ce95

% C

Ip-

Val

ue

Faci

al f

eatu

res

mea

sure

b

Fa

cial

phe

noty

pe r

ank

Ran

ks 1

and

2 (N

= 3

55)

106.

7R

efer

ence

107.

4R

efer

ence

104.

8R

efer

ence

Ran

ks 3

and

4 (N

= 1

0)10

2.5

−4.

2−

11.7

, 3.3

0.26

910

0.6

−6.

8−

16.6

,3.0

0.17

510

3.6

−1.

2−

7.6,

5.3

0.72

4

PF

L A

BC

-Sco

re

A (

>—

1 SD

) (N

= 4

10)

107.

2R

efer

ence

107.

7R

efer

ence

105.

2R

efer

ence

B (

>−

2 SD

& ≤

−1

SD)

(N =

57

)10

3.9

−3.

3−

6.6,

0.0

60.

055

102.

4−

5.3

−9.

6, −

1.0

0.01

510

4.4

−0.

9−

3.7,

2.0

0.55

3

C (

≤−2

SD)

(N =

22)

101.

3−

5.9

−11

.0, −

0.7

0.02

510

0.4

−7.

3−

13.8

, −0.

80.

027

102.

0−

3.2

−7.

7, 1

.30.

160

Ph

iltru

m A

BC

-Sco

re

A (

Ran

k 1

or 2

) {N

= 2

60)

107.

8R

efer

ence

107.

9R

efer

ence

106.

1R

efer

ence

B (

Ran

k 3)

(N=

314)

105.

5−

2.3

−4.

4, −

0.2

0.03

410

5.6

−2.

2−

5.0,

0.5

0.11

510

4.3

−1.

8−

3.6,

−0.

070.

041

C (

Ran

k 4

or 5

) (N

= 7

3)10

4.1

−3.

5−

6.9,

−0.

10.

042

104.

3−

3.4

−7.

6, 0

.80.

116

103

−2.

9−

5.8,

−0.

030.

048

U

pper

Lip

AB

C-S

core

A (

Ran

k 1

or 2

)(N

= 10

2)10

5.9

Ref

eren

ce10

7.3

Ref

eren

ce10

3.4

Ref

eren

ce

B (

Ran

k 3)

(N =

174

)10

6.0

0.1

−3.

2, 3

.40.

950

106.

7−

0.7

−4.

9, 3

.50.

757

104.

10.

7−

2.0,

3.4

0.61

3

C (

Ran

k 4

or 5

) (N

= 1

88)

107.

21.

3−

1.7,

4.3

0.38

810

6.9

−0.

5−

4.4,

3.4

0.81

010

6.0

2.5

0.06

, 5.0

0.04

5

PFL

, pal

pebr

al f

issu

re le

ngth

.

a IQ m

easu

red

with

WPP

SI-R

.

b Face

Ran

ks a

nd A

BC

-Sco

res

desc

ribe

d in

Fig

. 1.


l features related to fetal alcohol syndrome in 5-year-old

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